Phenothiazines have been shown to possess antihistaminic, sedative, anti-motion-sickness, antiemetic, and anticholinergic effects. They are generally indicated for: 1) amelioration of allergic reactions to blood or plasma; 2) in anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled; 3) for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated; 4) active treatment of motion sickness; 5) preoperative, postoperative, and obstetric (during labor) sedation; 6) prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery; 7) as an adjunct to analgesics for the control of postoperative pain; 8) for sedation and relief of apprehension and to produce light sleep from which the patient can be easily aroused; and 9) intravenously in special surgical situations, such as repeated bronchoscopy, ophthalmic surgery, and poor-risk patients, with reduced amounts of meperidine or other narcotic analgesic as an adjunct to anesthesia and analgesia. Phenothiazines are also indicated as tranquilizers in veterinary medicine. Recently, phenothiazines have been shown to be inhibitors of KSP kinesin which is involved in microtubule-mediated mitotic spindle-related distribution of replicate copies of the genome to each daughter cell that result from cell division. Therefore, phenothiazines may have a role in cancer treatment as well. However, with the use of phenothiazines some incidents of venous thrombosis at the injection site have been encountered. Other clinical case reports involving the use of promethazine HCl have indicated irritation and other serious adverse reactions at the local area of injection particularly gangrene at the extremity of the injection site. Promethazine hydrochloride has also been reported to raise plasma creatine kinase levels after intramuscular injection, which is an indication of muscle irritation.
Therefore, pharmacotherapy with phenothiazines would be improved if these and/or other side effects associated with their use could be decreased or if their pharmacology may be improved. Thus, there is a large unmet need for developing novel phenothiazine compounds.
The present invention seeks to address these and other needs in the art.